Abstract: Head and neck cancer (HNC) affects the lives of nearly half a million people in low-and-middle- income countries (LMICs) annually resulting in over 250,000 deaths. While surgery and radiotherapy are the mainstays of effective treatment in high-income countries (HICs), access to these treatment modalities in LMICs is limited to under 10% of the population. The low cost and portability of ablative techniques makes them well-poised to provide the efficacy of surgery and radiotherapy that are commonplace in HICs to the resource-limited settings of LMICs. While current ablative techniques are either expensive, electricity- dependent, or not portable, our group has developed a novel technique that is suited for the demands of LMICs. This technique (termed ?enhanced ethanol ablation?) is a modification of ethanol ablation, which has been used extensively in the treatment of unresectable hepatocellular carcinomas. Enhanced ethanol ablation involves the direct injection of ethyl cellulose-ethanol into malignant tissue. Ethyl cellulose (generally regarded as safe by the FDA) is ethanol-soluble and forms a viscous solution which can be injected through a standard needle but is water-insoluble and forms an ethanol-rich gel upon contact with the aqueous environment of biological tissue. In a proof-of-concept study with oral squamous cell carcinoma tumors in the hamster cheek pouch, 7 of 7 tumors completely regressed when treated with enhanced ethanol ablation. Due to the superficial nature of HNCs, shallow needle insertion depths must be used to spare underlying healthy tissue. Shallow insertion depths increase the risk of backflow (flow out of the tumor along the needle pathway). To minimize backflow, the needle insertion rate must be optimized to limit tissue damage during needle insertion to maximize the force exerted on the needle by the tissue. Since HNCs have a heterogenous mechanical environment, they are vulnerable to crack formation (flow out of the tumor into surrounding tissue caused by fluid-induced tissue damage) at sites of low fracture toughness (such as necrotic areas). Optimizing the fluid infusion rate can minimize fluid-induced tissue damage, ensuring lower rates of crack formation and increased injected fluid accumulation within the tumor. Upon optimizing the injection protocol, the injection volume must be tuned to induce necrosis throughout the entire tumor while sparing surrounding tissue. The central hypothesis of this proposal is that upon optimization of both the injection protocol and the dosage, enhanced ethanol ablation will be comparable to the standard-of-care (surgery) and the most common ablative therapy in LMICs (cryotherapy). This hypothesis will be addressed in three specific aims, all of which will utilize an immunocompetent rat model of oral SCCs. First, the injection protocol will be optimized to maximize injected fluid distribution within the tumor. Next, the injection volume will be tuned to ablate a clinically-relevant tumor volume and a 3 mm surrounding margin of tissue (to mimic clear resection margins in HNC). Finally, survival rates in enhanced ethanol ablation will be compared to surgical resection over a 90-day observation period.